---

---

---

WARNING LETTER

Ref.: 21-HFD-45-12-01

Dear Dr. Melnyk:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site from September 13 to September 14, 2021. Investigator Tawny L. Colling, representing FDA, reviewed your conduct of a clinical investigation (b)(4), performed for (b)(4).

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, Investigator Colling presented and discussed with you and your staff Form FDA 483, Inspectional Observations.

From our review of the FDA Establishment Inspection Report and the documents submitted with that report, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312) governing the conduct of clinical investigations. We wish to emphasize the following:

You failed to retain records required to be maintained under 21 CFR Part 312 for a period of two years following the date a marketing application is approved for the drug for the indication for which the drug is being investigated; or, if no application is filed or if the application is not approved for such indication, until two years after the investigation is discontinued [21 CFR 312.62(c)].

As a clinical investigator, you are required to retain records of the disposition of the drug, including dates, quantity, and use by subjects, and to retain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. You are required to retain these records for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or the application is not approved for such indication, until two years after the investigation is discontinued and FDA is notified.

You failed to adhere to these requirements. Specifically, for Protocol (b)(4), you failed to retain adequate and accurate case histories, including the following:

• Signed and dated informed consent forms for all (b)(4) randomized subjects
• Supporting data documenting medical history, study eligibility, adverse events, concomitant medications, progress notes, and visit assessments, including (b)(4), for 16 of the (b)(4) randomized subjects
• Case report forms for all (b)(4) randomized subjects

You were required to retain the study records for this protocol because a Biologics License Application had been filed for the indication under study, and the outcome of the application had not yet been determined (that is, approved or not approved) before you lost the study records.

During the inspection, you stated that all study records were stored in a locked archival room at your site, with access limited to your site personnel only. You stated that once the study was closed by the sponsor, all study records were packed into four boxes and placed into an archiving room. On August 2, 2021, the sponsor’s contract research organization arrived at your site to prepare for this FDA inspection, and noted that study records, including but not limited to the study records specified above, were missing. You explained that you searched other boxes to see if the study records had been misplaced, but you could not locate them. You also stated that the study monitor reviewed study records (subjects’ informed consent forms, medical histories, spirometry reports) during the study and at the closeout visit, and did not have any major comments regarding the documents.

You explained that your department had undergone a reorganization, which made conducting clinical studies more difficult. You suggested this may be why some study records were missing, even though your study staff were the only ones with access to the archival room. You noted that you have not been involved in clinical research since 2020, and that not being able to locate these records reinforced your decision to no longer conduct clinical research in the future.

While we acknowledge that you indicated that you do not plan to conduct clinical research in the future, you have not provided any details about how you personally plan to prevent similar violations from occurring if you should change your mind and decide to participate as a clinical investigator in a future clinical investigation. Your explanation, when taken into consideration with the violations described above, suggests systemic failures in your conduct of this clinical investigation.

Your failure to retain study records as required by FDA regulations significantly compromises the validity and integrity of data collected at your site.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.

Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to adequately address this matter may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at [email protected]. Your written response and any pertinent documentation should be addressed to:

Miah Jung, Pharm.D., M.S.
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Building 51, Room 5219
10903 New Hampshire Avenue
Silver Spring, MD 20993
U.S.A.

Sincerely yours,
{See appended electronic signature page}
David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

--------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
--------------------------------------------------------------------------------------------
/s/
------------------------------------------------------------
DAVID C BURROW
12/21/2021 10:49:32 AM